DESC:FIELD OF THE INVENTION
The present application provides a novel process for the preparation of Bexagliflozin, (2s,3r,4r,5s,6r)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2h-pyran-3,4,5-triol a SGLT2 inhibitor and its salts, hydrates, solvates and intermediates thereof, in high yields and purity and suitable for manufacturing in commercial scale.

Formula I

BACKGROUND OF THE INVENTION
Diabetes Mellitus continues to be a major non-communicable disease with global burden of 370 million at present and projected to increase to 480 to 590 million by 2030. Treatment of type 2 diabetes (T2DM) continues to present challenges, with significant proportion of patients failing to achieve and maintain glycemic targets.
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. SGLT2 inhibitors prevent the kidneys from re-absorbing glucose back into the blood by passing into the bladder. Glucose is re-absorbed back into the blood via the renal proximal tubules. SGLT2 is a protein predominantly expressed in the renal proximal tubules and is likely to be major transporter responsible for this uptake. Glucose-lowering effect of SGLT-2 inhibitors occurs via an insulin-independent mechanism mostly through glucosuria by increasing the urinary excretion of glucose. SGLT2 inhibitor indicated for the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease. Bexagliflozin is an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the compound is investigated in lowering hemoglobin Ale (HbAlc) levels in patients with type 2 diabetes mellitus (T2DM) and moderate renal impairment. The compound is for therapeutic intervention in diabetes and related disorders, SGLT2 is localized in the renal proximal tubule and is reportedly responsible for the majority of glucose reuptake by the kidneys and is marketed under the proprietary name Brenzavvy, Bexacat by THERAXOSBIO LLC is chemically named as (2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and has the following chemical structure

Formula I
Bexagliflozin shows pharmaceutical activity by functioning as a Sodium-glucose co-transporter-2 (SGLT-2) inhibitor and thus is indicated for the treatment of type 2 diabetes mellitus.
Several synthetic methods have been reported in the literature to prepare Bexagliflozin, (2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol and its intermediates.
U.S. Patent No.7838499 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme

WO2013152654 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

US9062087B2 discloses the below process to prepare compound of formula (I) as per the following synthetic scheme.

All the above prior art methods for the preparation of compound of formula (I) have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates. Accordingly, there remains a need for the industrial preparation of (2s,3r,4r,5s,6r)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol with high yield. Therefore, still there is need for the development of commercially viable, cost-effective process for the preparation of Bexagliflozin compound of formula (I).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, effective, and industrially feasible novel process for the preparation of Bexagliflozin, (2s,3r,4r,5s,6r)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol and its intermediates thereof which is cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy process and purification steps.
SUMMARY OF THE INVENTION
The improved and novel process for the preparation of Bexagliflozin, (2s,3r,4r,5s,6r)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol and its intermediates disclosed herein has the following advantages over the processes described in the prior arts:
i. The present invention relates to a novel process for the preparation of Bexagliflozin and also relates to novel intermediates in the preparation of Bexagliflozin;
ii. the comprehensive experimentation exemplifies an inventive and easily scaled-up synthetic technique;
iii. solvent recovery is a form of waste reduction eco-friendly and alternative to improving the greenness of industrial processes and which makes the process economic cost effective and environment friendly;
iv. reactions carried out at low temperatures reduced additional energy;reduced reaction time durations faster results;
v. using the cheap inexpensive alkali hydroxide and alkaline metal alkoxy base characterized in that said bases has a pKa value of from 10 to 20 in reaction is cost- effective;
vi. the present invention process produced a novel compound (5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone;
vii. the present invention process produced a novel compound (2-chloro-5-iodophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanol;
viii. the present invention process produced a novel compound 1-chloro-2-((4-(2-cyclopropoxyethoxy)phenyl)(methoxy)methyl)-4-iodobenzene;
ix. the present invention process produced a novel compound (((2S,3R,4S,5R,6R)-2-(4-chloro-3-((4-(2-cyclopropoxyethoxy) phenyl)(methoxy) methyl) phenyl)-2-methoxy-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(trimethylsilane);
x. Toluene has high recovery percentage in reaction; solvent recovered under vacuum, can be reused after distillation;
xi. in one aspect, the present invention relates to a novel process for the preparation of Bexagliflozin and its intermediates;
xii. use of phase transfer catalyst increases the reaction rate and reaction goes to completion in lesser time thus making the process economical and industrially feasible;
xiii. the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and multiple isolations;
the present invention provides a process for preparation of (2s,3r,4r,5s,6r)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol and its intermediate compounds which is faster and cost-effective and the overall yield of the product is increased also it is substantially pure.
In one aspect of the present invention relates to compounds of general formula VIIa

Formula VIIa
wherein
R denotes hydrogen, C1-C4 alkyl; R1 denotes cyclopropyl, cyclopentyl, cyclohexyl, R-tetrahydrofuran-3-yl, S-tetrahydrofuran 3-yl or tetrahydropyran-4-yl;
and X denotes Br or I.
In another specific embodiment the compound of formula (VIId)

Formula VIId
Wherein
X denotes I or Br; R denotes hydrogen, C1-C4 alkyl;
In one aspect of the present invention relates to a novel process for the preparation of compound of Formula I comprising the steps of:
(a) coupling of 5-bromo-2-chlorobenzoyl chloride as obtained from 5-bromo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of Lewis acid to get the compound of Formula IV;

Formula II Formula III
with or without isolation of compound of Formula IV;

Formula IV
(b) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of base and with or without phase transfer catalyst;

Formula B Formula V
(c) reducing the compound of Formula V to obtain compound of the Formula VI in
presence of reducing agent;

Formula VI

d) methylation of compound of Formula VI in methanol to obtain compound of the Formula VII in presence of appropriate acid;

Formula VII
(e) coupling of the compound of Formula VII with the compound of Formula D to obtain
compound of the Formula VIII;

Formula D Formula VIII
(f) reducing the compound of Formula VIII to obtain compound of the Formula IX L-proline complex in presence of appropriate reducing agent, Lewis acid and L-Proline;

Formula IX
(g) reacting a compound of formula IX in presence of methanol and water to obtain compound of Formula I;
Formula I
(h) optionally purifying the compound of Formula (I) in a suitable solvents or mixture thereof.
In another aspect of the present invention provides for the synthesis of a compound of the Formula VII comprising the steps of:

Formula (VII)

a) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in with or without phase transfer catalyst, and base, appropriate solvents to give compound of formula (V);

Formula (IV) Formula (V)

b)compound of formula (V) undergoes ketoreduction with appropriate metalborohydride reducing agents in presence of appropriate solvent gives compound of formula (VI);

Formula (VI)
c)compound of formula (VI) undergoes methylation in presence of acid and appropriate solvent gives compound of formula (VII);

Formula (VII)

d)optionally purifying the compound of formula (VII) in a suitable solvent or mixture of solvents thereof.
In further aspect of the present invention the compound of formula (Vb)

Formula (Vb)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In another aspect of the present invention the compound of formula (VIb)

Formula (VIb)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In further aspect of the present invention the compound of formula (VIIb)

Formula (VIIb)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In further aspect of the present invention the compound of formula (Vc)

Formula (Vc)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In another aspect of the present invention the compound of formula (VIc)

Formula (VIc)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In further aspect of the present invention the compound of formula (VIIc)

Formula (VIIc)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In another aspect of the present invention the compound of formula (VIII)

Formula (VIII)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In another aspect of the present invention provides a compound or pharmaceutically acceptable salts or stereoisomer thereof; wherein the compound is selected from:
(3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
1-chloro-2-((4-(2-cyclopropoxyethoxy)phenyl)(methoxy)methyl)-4-iodobenzene;
2-(2-chloro-5-iodophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanol;
3-(2-chloro-5-iodophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone;
(5-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone;
(6-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanol and
4-bromo-1-chloro-2-((4-(2-cyclopropoxyethoxy)phenyl)(methoxy)methyl)benzene.

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly indictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method, or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.

The term “one-pot” or "in-situ" typically means "in the reaction mixture" or "not in isolated form" or "existing as residue".

In one embodiment the following Scheme-1 describes the process for the preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol compound of formula (I)

Scheme 1
In one embodiment of the present invention relates to a novel process for the preparation of Bexagliflozin of Formula I comprising the steps of:
a)coupling of 5-bromo-2-chlorobenzoyl chloride as obtained from 5-bromo-2- chlorobenzoic acid of Formula II, with fluorobenzene of Formula III in presence of Lewis acid to get the compound of Formula IV;

Formula II Formula III
with or without isolation of compound of Formula IV;

Formula IV
(b) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of base and with or without phase transfer catalyst;

Formula B Formula V
(c) reducing the compound of Formula V to obtain compound of the Formula VI in
presence of reducing agent;

Formula VI

d) methylation of compound of Formula VI in methanol to obtain compound of the Formula VII in presence of appropriate acid;

Formula VII
(e) coupling of the compound of Formula VII with the compound of Formula D to obtain
compound of the Formula VIII;

Formula D Formula VIII
(f) reducing the compound of Formula VIII to obtain L-Proline complex compound of the Formula IX in presence of appropriate reducing agent, Lewis acid and L-Proline;

Formula IX
(g) a compound of Formula I obtained in presence methanol and water;
Formula I
(g) optionally purifying the compound of Formula (I) in a suitable solvents or mixture thereof.
In step (a), coupling of 5-bromo-2-chlorobenzoyl chloride compound of Formula IV obtained from 5-bromo-2-chlorobenzoic acid of Formula II, with fluorobenzene of Formula III is carried out in presence of Lewis acid such as Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride, Zirconium chloride, Boron trifluoride and the like; preferably aluminum chloride. 5-Bromo-2-chlorobenzoic acid of Formula II is converted into 5-bromo-2-chlorobenzoyl chloride using chlorinating agent such as Oxalyl chloride, Thionyl chloride and the like. This reaction is carried out in presence of solvents selected from the group comprising of dichloromethane, chlorobenzene, nitrometane, toluene and dimethylformamide, dimethyl sulfoxide and the like.

In step (b), coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B is carried out to obtain compound of Formula V. This coupling is carried out under basic conditions as nucleophilic substitution reaction. Suitable base for this coupling reaction is selected from the group comprising of alkali or alkaline earth metal salts, in particular carbonates, hydroxides, alkoholates and metal hydrides such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and calcium hydride; preferably potassium carbonate, sodium hydroxide, sodium methoxide, potassium tert-butoxide and sodium hydride; and more preferably potassium hydoxide. The solvent is selected from the group comprising of polar and non-polar solvents, acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene and dimethylsulfoxide, tetrahydrofuran, 2-methyl THF, xylene, dioxane, such as acetonitrile, ethanol, isopropanol, butanol, acetone, water, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, and mixtures thereof. The catalyst can be a phase transfer catalyst selected from tetrabutylammoniumbromide (TBAB), tetrabutylammonium fluoride (TBAF), TBAHS(Tetrabutylammonium hydrogensulfate), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA).

In step (c), reduction of the compound of Formula V is carried out in presence of Suitable reducing agent to obtain compound of the Formula VI; Suitable reducing agent is selected from the group comprising of silane such as triethyl silane and tri isopropylsilane, tetramethyldisiloxane, tripropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride borohydride such as sodium borohydride; and aluminum hydride such as lithium aluminum hydride; preferably tetramethyldisiloxane, triethyl silane, sodium borohydride. The reactions are preferably carried out in solvents selected from the group comprising of methanol, ethanol, isopropanol, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, acetone, toluene, dimethyl sulfoxide, dimethyl acetol, dimethylformamide, benzene, hexane, acetonitrile, ethanol, isopropanol, diglyme, monoglyme, N-methylpyrollidone, toluene and dimethyl sulfoxide mixture, tetrahydrofuran, 2-methyl THF, xylene, dioxane and mixtures thereof.

In step (d) methylation of compound of formula VI to obtain compound of formula VII by treating it with an alcohol or water. The alcohol is selected from the group comprising of C1-4 alkanol, such as methanol or ethanol. This conversion reaction is performed in presence of an acid such as acetic acid, methane sulfonic acid, toluene sulfonic acid, sulfuric acid, trifluoroacetic acid and hydrochloric acid preferably methane sulfonic acid.

In step (e), firstly compound of Formula VII undergoes either halogen-metal exchange reaction or direct insertion of the metal into the carbon halogen bond and then finally get coupled with glucolactone compound of formula D to give compound of the Formula VIII. The Grignard or Lithium derivative of compound of Formula VII are preferred. The halogen-metal exchange to synthesize the corresponding lithium derivative of compound VII may be carried out with an organo-lithium compound such as n- butyllithium, sec-butyllithium or tert-butyllithium and Hexamethylphosphoramide. The analogous magnesium compound may also be generated by a halogen-metal exchange with a suitable Grignard reagent such as C3-C4- alkyl magnesium chloride or bromide, for example isopropyl- or sec-butyl magnesium bromide or chloride or di-isopropyl- or di-sec-butyl magnesium without or in the presence of an additional salt such as e.g. lithium chloride. The organo-magnesium compound may also be generated in situ from suitable precursors. The halogen-metal exchange reaction is carried out in the solvent selected from the group comprising of diethyl ether, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, hexane, dimethyl sulfoxide, dichloromethane or mixtures thereof and preferably tetrahydrofuran, diethylene glycol dimethyl ether, hexane and mixtures thereof. Alternatively, the metal derivative of compound VIII is prepared by directly inserting a metal into the carbon-halogen bond of the compound of Formula VII. Lithium or magnesium are suitable elemental metals for this insertion. This insertion reaction is carried out in solvents selected from the group comprising of diethyl ether, dioxane, tetrahydrofuran, 2-Methyl tetrahydrofuran, toluene, hexane, dimethyl sulfoxide and mixtures thereof. Finally, this metal derivative of compound VII get coupled with glucolactone compound of formula D to give compound of the Formula VIII. This coupling reaction is carried out in solvents selected from the group comprising of diethyl ether, di isopropyl ether, methyl tert-butyl ether, toluene, methylene chloride, hexane, tetrahydrofuran, 2-Methyl tetrahydrofuran, dioxane, N-methylpyrrolidone and mixtures thereof.

In step (f), the compound of Formula VIII is reduced and to form complex with proline of Formula IX. The reducing agent is selected from the group comprising of silanes such as triethyIsilane, tri-n-propylsilane, triisopropylsilane, or diphenylsilane; hydrides such as sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride, Hydrogen with transition metal catalyst etc. This reduction reaction is carried out with or without Lewis acid. The Lewis acid is selected from the group comprising of boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid and acetic acid; preferably boron trifluoride etherate. The reaction may be carried out in a solvent selected from the group comprising of methylene chloride, chloroform, acetonitrile, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof and proline is L-Proline for complex formation. The solvent is preferably selected in view of the reducing agent and the optional Lewis acid. One particularly suitable combination of reagents comprising of triethylsilane and boron trifluoride etherate; preferably triethylsilane, which is conveniently used in acetonitrile.

In step (g), compound of Formula IX is optionally purified to give pure Bexagliflozin of Formula I. This purification is carried out by techniques already known in prior art such as crystallization. The solvent used for purification is selected from the group comprising of C1-4 alkanols, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof. Preferred solvents are selected from the group comprising of methanol, ethanol, isopropanol, water, ethyl acetate, acetonitrile, acetone, diethyl ether and mixture thereof.

In another embodiment the following Scheme-1 describes the process for the preparation of compound of formula (VIII)

Wherein X denotes Br or I
Scheme 2

In one embodiment of the present invention relates to compounds of general formula VIa

Formula VIIa
wherein
R denotes C1-C4 alkyl; R1 denotes cyclopropyl, cyclopentyl, cyclohexyl, R-tetrahydrofuran-3-yl, S-tetrahydrofuran 3-yl or tetrahydropyran-4-yl;
and X denotes Br or I.
In another specific embodiment the compound of formula (VIIb)

Formula VIIb

Wherein
X denotes I or Br; R denotes hydrogen, C1-C4 alkyl;
In further specific embodiment the compound of formula (VIIc)

Formula VIIc
In another embodiment of the present invention relates to a novel process for the preparation of Formula VII comprising the steps of:

Formula (VII)

a) compound of formula (IV) undergoes coupling reaction with 2-cyclopropoxyethan-1-ol of Formula B in with or without phase transfer catalyst, and base, appropriate solvents to give compound of formula (V);

Formula (IV) Formula (V)

b) compound of formula (V) undergoes ketoreduction with appropriate metalborohydride reducing agents in presence of appropriate solvent gives compound of formula (VI);

Formula (VI)
c)compound of formula (VI) undergoes methylation acid and appropriate solvent gives compound of formula (VII);

Formula (VII)

d)optionally purifying the compound of formula (VII) in a suitable solvent or mixture of solvents thereof.
In one specific embodiment of the present invention the compound of formula (V)

Formula (V)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In one specific embodiment of the present invention the compound of formula (VI)

Formula (VI)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In another specific embodiment of the present invention the compound of formula (VII)

Formula (VII)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In further specific embodiment of the present invention the compound of formula (VIII)

Formula (VIII)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In one specific embodiment the compound of formula (Va)

Formula Va
Wherein X denotes I or Br.
In one specific embodiment the compound of formula (Vb)

Formula Vb
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In another specific embodiment the compound of formula (VIb)

Formula VIb
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In another specific embodiment the compound of formula (VIIb)

Formula VIIb
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.

In another embodiment of the present invention the compound of formula (VIc)

Formula (VIc)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.
In further embodiment of the present invention the compound of formula (VIIc)

Formula (VIIc)
produced by the aforesaid process is a novel compound and is therefore provided as a further feature of the present invention.

In further specific embodiment the compound of formula (VIII)

Formula (VIII)
In step (a), coupling of 5-bromo-2-chlorobenzoyl chloride obtained from 5-bromo-2- chlorobenzoic acid of Formula II with fluorobenzene of Formula III is carried out in presence of Lewis acid such as Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride, Zirconium chloride, Boron trifluoride and the like; preferably aluminum chloride. 5-Bromo-2-chlorobenzoic acid of Formula II is converted into 5-bromo-2-chlorobenzoyl chloride using chlorinating agent such as Oxalyl chloride, Thionyl chloride and the like. This reaction is carried out in presence of solvents selected from the group comprising of dichloromethane, chlorobenzene, nitrometane, toluene, and dimethylformamaide and the like.

In step (b), coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B is carried out to obtain compound of Formula V. This coupling is carried out under basic conditions as nucleophilic substitution reaction. Suitable base for this coupling reaction is selected from the group comprising of alkali or alkaline earth metal salts, in particular hydroxides, carbonates, metal hydrides and alkoholates such as potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride; preferably potassium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium hydride; The solvent is selected from the group comprising of polar and non-polar solvents, such as acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene and dimethylsulfoxide, tetrahydrofuran, 2-methyl THF, xylene, dioxane, dichloromethane, toluene, acetonitrile and mixtures thereof.

In step (c), ketoreduction of the compound of Formula V is carried out to obtain compound of the Formula VI Suitable reducing agent is selected from the group comprising of silane such as triethyl silane and tripropylsilane, triisopropylsilane, tetramethyldisiloxane polymethylhydrosiloxane; borohydride such as sodium borohydride; and aluminum hydride such as lithium aluminum hydride; preferably tetramethyldisiloxane, triethyl silane, polymethylhydrosiloxane. This reduction is preferably carried out in the presence of a Lewis acid such as boron trifluoride etherate, aluminum chloride, tris(pentafluorophenyl) borane, trifluoroacetic acid and hydrochloric acid. The reactions are preferably carried out in solvents selected from the group comprising of halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, toluene, benzene, hexane, diglyme, monoglyme, acetone, toluene and dimethyl sulfoxide mixture, 2-methyl THF, THF, tert-butanol, acetonitrile, xylene, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methyl-2-pyrrolidone and mixtures thereof.

In one embodiment, the metal hydride reducing agents employed in the process of ketoreduction are selected from sodium borohydride, lithium borohydide, sodium cyano borohydide, lithium aluminum hydride, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tributoxyaluminum hydride, lithium dibutoxyaluminum hydride, lithium diethylaluminum hydride, lithium triethylaluminum hydride, diisobutylaluminum hydride, and tri-n- butyltin hydride more preferably sodium borohydride.
In further embodiment, the said Lewis acid is selected form Aluminum chloride, Zinc chloride, Ferric chloride, Titanium chloride, Zirconium chloride, BF3-OEt2, BF3.

In certain embodiment, the base for coupling reaction is selected from the group comprising of alkali hydroxide or metal hydride; wherein the base characterized in that said base has a pKa value of from 10 to 20.

In further embodiment, the alkali hydoxide and alkaline metal alkoxy base for coupling reaction is selected from potassium hydroxide, lithium hydroxide, lithium tert-butoxide, lithium ethoxide, lithium methoxide, potassium tert-butoxide, potassium ethoxide, potassium methoxide, sodium tert-butoxide, sodium ethoxide and sodium methoxide more preferably potassium hydroxide or mixture thereof.

In another embodiment, coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of base and with or without phase transfer catalyst.
In further embodiment, coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of phase transfer catalyst and base.
In further specific embodiment, coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of base.
In further embodiment, the phase transfer catalyst can be selected from tetrabutylammonium bromide (TBAB), TBAHS (Tetrabutylammonium hydrogensulfate), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA).
In another embodiment, the said keto reduction reducing agent organosilane is selected form 1,1,3,3-tetramethyldisiloxane, (Et)3SiH, triisopropylsilane, polymethylhydrosiloxane, tris(trimethylsilyl)silane and diphenylsilane or mixture thereof.

In specific embodiment, the said dipolar aprotic solvent is selected from toluene, diglyme, monoglyme, acetone, toluene and dimethyl sulfoxide, 2-methyl THF, THF, tert-Butanol, dichloromethane, dichloroethane, isopropyl acetate, ethyl acetate, acetonitrile, xylene, toluene, benzene, heptane, cyclohexane, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-Methyl-2-pyrrolidone or mixture thereof.
In further specific embodiment of the present invention provides a compounds or pharmaceutically acceptable salts or stereoisomers thereof; wherein the compound is selected from:
(3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
4-chloro-2-((4-(2-cyclopropoxyethoxy)phenyl)(methoxy)methyl)-4-iodobenzene;
5-(2-chloro-5-iodophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanol;
6-(2-chloro-5-iodophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone;
(7-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanone;
(8-bromo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl)methanol and
4-bromo-1-chloro-2-((4-(2-cyclopropoxyethoxy)phenyl)(methoxy)methyl)benzene.
The process for the preparation of Bexagliflozin described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt followed by optionally washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An antisolvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.

Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
In another embodiment, the below are the abbreviations are used in the specification.
AlCl3- Aluminium Chloride anhydrous, HCl- Hydrochloric acid, DCM-Dichloromethane, TEA- Triethyl amine, DIPEA- Diisopropyl ethylamine, KOH-Potassium hydroxide, NaBH4-Sodium borohydride, NaOtBu-Sodium tertiary butoxide, KOtBu-Potassium tertiary butoxide, BF3etherate- boron trifluoride-ether complex, SOCl2- Thionylchloride, C2O2Cl2-Oxallylchloride, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography, THF-Tetrahydrofuran, 2-Methyl-THF-2-Methyltetrahydrofuran, TES-Triethylsilane, TMDS-Tetramethyl disiloxane, TBAB-tetrabutylammonium bromide, TBAF-tetrabutylammonium fluoride, TBAH-tetrabutylammonium hydroxide, TEBA-Triethylbenzylammonium chloride, TBAHS-Tetrabutylammonium hydrogensulfate, TMDSO-Tetramethyl disiloxane, (Et)3SiH- Triethylsilane, MDC-Methylene Dichloride, DMSO-Dimethyl sulfoxide, DMF-Dimethylformamide, NaOH-Sodium hydroxide, Na2CO3-Sodiumcarbonate, NBL-n-Butyllithium, HMPA-Hexamethyl phosphoramide, NaH-Sodium hydride, MeOH-Methanol, EtOAc-Ethyl acetate, H2O-Water, ACN-acetonitrile, Monoglyme-Dimethoxyethane, Diglyme-1-Methoxy-2-(2-methoxyethoxy)ethane, ND-not detected, SM-starting material and SMI-Single maximum impurity.

EXAMPLES
Example-1: Preparation of (5-Iodo-2-chlorophenyl) (4fluorophenyl) methanone:
100.0gm of 5-Iodo-2-chlorobenzoic acid was added to 300 gm of dichloromethane, then 1.0g of DMF was added, the reaction temperature was controlled to 5-10°C, 120.0gm (2.2eq) of Oxalyl chloride was added dropwise, and after the dropwise addition was completed, the mixture was stirred and dissolved. Atmospheric distillation to recover dichloromethane for use in the next batch of this step. After distillation, 100.0ml of dichloromethane was added to obtain an acid chloride solution, which was stirred and dissolved to be clear for use. 500.0ml of dichloromethane, 61.0gm of anhydrous aluminium trichloride and 150.0gm of Fluoro benzene were alum added to the reaction mass at cooling condition and the reaction temperature was controlled at -10 to 10°C, and the dichloromethane solution of the acid chloride prepared above was added dropwise. After completion of reaction mass quench with 500.0ml of water .Finally organic layer wash with 2x100ml of water, and dichloromethane is recovered at normal pressure, which can be reused after distillation. After distillation, crude diluted with methanol/Isopropyl alcohol and cooled to isolate as the tittle product of yield 115.0gm, purity 99.6%.
Example-2: Preparation of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methanone
Under the protection of nitrogen, 500ml of Toluene, 100g of (5-Iodo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(Cyclopropyloxy)ethanol were added and TBAB, and the temperature was reduced to 0-5°C. Then charged 45.0 g(2.5eq) of potassium hydroxide powder as lot wise at control the temperature 0-10?.After addition keep the temperature and stir for 2 hours. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer was separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 300.0ml of methanol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 50°C to obtain 105g (87.51%) product of title product. Product with a purity (HPLC) of 99.16% and a single maximum impurity of 0.05%.
Example-2.1: Preparation of (5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy)phenyl) methanone
Under the protectionof nitrogen, 500ml of Toluene, 110 ml DMF, 100g of (5-Iodo-2-chlorophenyl)(4-fluorophenyl)methanone and 35.0g of 2-(Cyclopropyloxy)ethanol were added and TBAB, and the temperature was reduced to 0-5°C. Then charged 45.0 g (2.5eq) of potassium hydroxide powder as lot wise at control the temperature 0-10?.After addition keep the temperature and stir for 2 hours. After the reaction was completed, the reaction solution was transferred to 300 ml water for quenching. The organic layer was separated by standing, and the organic layer was concentrated and dried under reduced pressure. Charge 300.0ml of methanol and stir to dissolve it then lower the temperature and filter with suction to obtain a wet and dry for 8 hours at 50°C to obtain 110g (93.6%) product of title product. Product with a purity (HPLC) of 99.38% and a single maximum impurity of 0.05%.
Example-3: Prepartion1-chloro-2-((4-(2-cyclopropoxyethoxy)phenyl)(methoxy)methyl)-4-iodobenzene
(5-iodo-2-chlorophenyl)(4-(2-cyclopropoxyethoxy) phenyl) methanone (100 g) was added to methanol (100 ml). Sodium borohydride (2.56 g, 0.30 eq) was then added lot-wise at 20-25ºC. After completion of the reaction Thereafter, HCl (100 g) diluted in methanol (500 ml) was added slowly and stirring was continued at 20-30ºC. After completion of reaction, the pH of reaction mass was adjusted to 7.5with aqueous sodium carbonate solution. Layer on concentrated under reduced pressure while maintaining the temperature below 50ºC. Obtained residue was diluted with water (600 ml) and the product was extracted with Ethyl acetate (1 x 500 ml). Obtained combined organic layer was washed with 7% aqueous sodium chloride, concentrated and crystallized in isopropyl alcohol to yield 1-chloro-2-((4-(2-cyclopropoxyethoxy)phenyl)(methoxy)methyl)-4-iodobenzene compound (110 g).
Example-4: Preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol( Bexaglifazolin)
To the solution of l-iodo-2-(4-(2-cyclopropoxyethoxy)benzyl)-4-nromobenzene in tetrahydrofuran, n-BuLi (2.5 mol) in hexane is added at a rate that maintains the reaction temperature below -80°C followed by addition of 2.2 eq of 2,3,4,6-tetra-0-trimethylsilyl-D- glucolactone in toluene at a rate to maintain the reaction temperature below -90°C. The solution is stirred for 60-90 min at -90°C .After TLC complies the addition of methane sulfonic acid in methanol. The reaction mass is stirred till completion of reaction at 25°C to 35°C. After completion of reaction, the reaction is quenched by the addition of sodium carbonate and distilled out under vacuum. To the obtained residue water is added and extracted with ethylacetate. The combined ethylacetate fractions are washed with brine and dried over sodium sulfate. The reaction mixture is concentrated to get the compound of formula (3R,4S,5S,6R)-2-(4-chloro-3-((4-(2-cyclopropoxyethoxy) phenyl)(methoxy)methyl) phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol. To the MDC solvent, 2.8eq of aluminium chloride (or) BF3 etherate is added in and cooled the mass to the temperature -20°C to -25°C. To the triethyl silane was added followed by addition Stirred the reaction mass for about 2 h., the reaction is quenched by addition of aqueous hydrochloric acid solution. Aqueous layer is extracted with methylenechloride. Combined organic layer is washed with 5% aqueous hydrochloric acid solution followed by water and brine. To the crude product was added L-proline 2.4 eq in ethanol/water and the mixture was stirred at 70° C. for 1 h until it became a clear solution. MTBE was added dropwise over 50 min, while the temperature was maintained at about 50° C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with Ethanol , hexane (2×300 mL), and dried at 40° C. under vacuum for to give a white solid (103.0 g HPLC purity 99.45% ).
Charge 100.0gm of L-Proline salt in 500.0ml of methanol an heating given up to 65°C and then added water to the reaction mass .After addition cool the reaction mass to 25-35°C and maintained for 16.0hrs.After maintence cool to 0-5°C.and filtered and then dried to get the Bexaglifazolin(55.0gm, HPLC purity 99.7%).
,CLAIMS:1. A method for preparation of benxagliflozin compound of Formula I

Formula I
comprising:
a)coupling of 5-bromo-2-chlorobenzoyl chloride as obtained from 5-bromo-2- chlorobenzoic acid of Formula II with fluorobenzene of Formula III in presence of Lewis acid to get the compound of Formula IV;

Formula II Formula III
with or without isolation of compound of Formula IV;

Formula IV
(b) coupling of the compound of Formula IV with 2-cyclopropoxyethan-1-ol of Formula B to obtain compound of Formula V in presence of base and with or without phase transfer catalyst;

Formula B Formula V
(c) reducing the compound of Formula V in presence of suitable reagent to obtain compound of the Formula VI in
presence of reducing agent;

Formula VI
(d) methylation of compound of Formula VI in methanol to obtain compound of the Formula VII in presence of appropriate acid;

Formula VII
(e) contacting the compound of Formula VII with glucolactone compound of formula D in presence of an organo-lithium compound and a solvent to obtain a compound of Formula Formula VIII;

Formula D Formula VIII
(f) reducing the compound of Formula VIII to obtain L-Proline complex compound of the Formula IX in presence of appropriate reducing agent, Lewis acid and L-Proline;

Formula IX
(g) a compound of Formula I obtained in presence methanol and water;
Formula I
(h) optionally purifying the compound of Formula (I) in a suitable solvents or mixture thereof.
2. The method as claimed in claim 1, wherein the Lewis acid in step a) is selected from a group consisting of aluminum chloride, zinc chloride, ferric chloride, titanium chloride, zirconium chloride, boron trifluoride and combination thereof.
3. The method as claimed in claim 1, wherein the base in step b) is selected from a group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride and calcium hydride and combination thereof.
4. The method as claimed in claim 1, wherein the solvent in step b) is selected from a group consisting of acetonitrile, ethanol, isopropanol, butanol, acetone, toluene, water, dimethylformamide, dimethylacetamide, diglyme, monoglyme, N-methylpyrollidone, toluene, dimethylsulfoxide, tetrahydrofuran, 2-methylTHF, xylene, dioxane, dichloromethane and combination thereof.
5. The method as claimed in claim 1, wherein the catalyst in step b) is selected from a group consisting of a tetrabutylammoniumbromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), Triethylbenzylammonium chloride (TEBA) and combination thereof.
6. The method as claimed in claim 1, wherein the reducing agent in step c) is selected from a group consisting of triethyl silane, tri isopropylsilane, tetramethyldisiloxane, tripropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, lithium aluminum hydride, diisobutylaluminum hydride borohydride and combination thereof.
7. The method as claimed in claim 1, wherein the Lewis acid in step c) is selected from a group consisting of boron trifluoride etherate, tris(pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid, aluminum chloride and combination thereof.
8. The method as claimed in claim 1, wherein the solvent in step c) is selected from a group consisting of dichloromethane, 1,2-dichloroethane, acetone, toluene, dimethyl sulfoxide, dimethyl acetol, dimethylformamide, benzene, hexane, acetonitrile, ethanol, isopropanol, diglyme, monoglyme, N-methylpyrollidone, tetrahydrofuran, 2-methylTHF, xylene, dioxane and combination thereof.
9. The method as claimed in claim 1, wherein the organo-lithium compound in step e) is selected from a group consisting of n-butyllithium, sec-butyllithium or tert-butyllithium and Hexamethylphosphoramide and combination thereof.
10. The method as claimed in claim 1, wherein the solvent is selected from a group consisting of diethyl ether, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, hexane, dimethyl sulfoxide, dichloromethane and combination thereof.
11. The method as claimed in claim 1, wherein the acid is selected from a group consisting of acetic acid, methane sulfonic acid, toluene sulfonic acid, sulfuric acid, trifluoroacetic acid, hydrochloric acid and combination thereof.